Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

Abstract

ABSTRACT Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis characterized by the presence of IgA immune complexes in the glomeruli. Recently, a multihit model has been proposed to describe the pathogenesis of IgAN, but it is believed that further predisposing factors are present, including immunological, genetic and environmental factors. Newly, the role of IL-6 in pathogenesis is becoming increasingly important but reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA. Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non-IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain caused the activation of CREB by PKR, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, both in IgAN and in TP-IgAN patients. PKR is normally activated by bacterial and viral RNA and we found that both the RNA poly(I:C), the and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients. In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.